Glecaprevir/pibrentasvir

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Glecaprevir/pibrentasvir
Glecaprevir and pibrentasvir.svg
Combination of
Glecaprevir NS3/NS4A inhibitor
Pibrentasvir NS5A inhibitor
Clinical data
Trade names Mavyret, Maviret, others
AHFS/Drugs.com Monograph
MedlinePlus a617039
License data
Pregnancy
category
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only) [2]
  • US: ℞-only
  • EU:Rx-only
  • In general: ℞ (Prescription only)
Identifiers
KEGG

Glecaprevir/pibrentasvir (G/P), sold under the brand names Mavyret and Maviret, is a fixed-dose combination medication used to treat hepatitis C. [3] [4] It contains glecaprevir and pibrentasvir. [4] [5] It works against all six types of hepatitis C. [3] At twelve weeks following treatment between 81% and 100% of people have no evidence of hepatitis C. [6] It is taken once a day by mouth with food. [3] [4]

Contents

The most common side effects are headache, diarrhea, and tiredness. [6] [7] In those with a history of hepatitis B, reactivation may occur. [7] It is not recommended in people with moderate to severe liver disease. [6] Glecaprevir works by blocking the protein NS3/4A protease, while pibrentasvir works by blocking NS5A. [3]

The combination was approved for medical use in the United States and Europe in 2017. [5] [3] It is on the World Health Organization's List of Essential Medicines. [8]

Medical uses

In the United States, G/P is used to treat adults and children aged 12 years and older or weighing at least 99 pounds with chronic hepatitis C virus (HCV) genotypes 1–6 and both without cirrhosis and with compensated cirrhosis who have not been previously treated for HCV (treatment-naïve). [6] [4] It is also used to treat adults and children aged 12 years and older or weighing at least 99 pounds with chronic HCV genotype 1 infection who have previously been treated with a NS5A inhibitor or a NS3/4A inhibitor but not both. [4] The duration of treatment was shortened from 12 weeks to eight weeks for many people in 2019. [6]

In the European Union, it is used to treat adults and adolescents aged 12 years and older with chronic (long-term) hepatitis C. [3]

Side effects

The only known side effects of G/P are hepatitis B reactivation, and more commonly headache, nausea, tiredness, and diarrhea. [9]

Mechanism of action

Glecaprevir inhibits NS3/4A, a serine protease, and pibrentasvir inhibits NS5A, a zinc-binding hydrophilic phosphoprotein. Both of these proteins are essential in hepatitis C viral RNA replication, which can no longer take place upon inhibition of these proteins. [9]

History

The development of G/P as a combination treatment was done by AbbVie and is in accordance with good manufacturing practice (GMP) standards, per the FDA. [9]

Initial identification of glecaprevir was done in a joint effort by AbbVie and Enanta Pharmaceuticals. [10] Enanta had a Collaborative Development and License Agreement with AbbVie for the identification and development of paritaprevir and glecaprevir, two HCV NS3 and NS3/4A protease inhibitors, that lasted from October 2016 to June 2017. In this agreement, Enanta received a total of US$427,000 in the form of license payments, proceeds from a sale of preferred stock, research funding payments, milestone payments, and royalties. [11]

The identification and development of pibrentasvir was done by AbbVie. [12]

Research

During clinical trials, G/P was shown to be effective at clearing all six genotypes of HCV from the blood. Over the course of eight studies involving greater than 2,300 patients with hepatitis C, 99% of non-cirrhotic patients with genotype 1 were negative for HCV after the eight-week treatment regimen. Of cirrhotic patients from the same group, 97% tested negative for HCV on a 12-week treatment regimen and the results were reportedly similar for the treatment of genotypes 2 and 4–6, whereas 95% of patients with genotype 3 HCV tested negative for the virus after treatment. [9]

Related Research Articles

<span class="mw-page-title-main">Hepatitis C</span> Human viral infection

Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. Early symptoms can include fever, dark urine, abdominal pain, and yellow tinged skin. The virus persists in the liver, becoming chronic, in about 70% of those initially infected. Early on, chronic infection typically has no symptoms. Over many years however, it often leads to liver disease and occasionally cirrhosis. In some cases, those with cirrhosis will develop serious complications such as liver failure, liver cancer, or dilated blood vessels in the esophagus and stomach.

<span class="mw-page-title-main">Boceprevir</span> Chemical compound

Boceprevir is a protease inhibitor used to treat hepatitis caused by hepatitis C virus (HCV) genotype 1. It binds to the HCV nonstructural protein 3 active site.

<span class="mw-page-title-main">Telaprevir</span> Chemical compound

Telaprevir (VX-950), marketed under the brand names Incivek and Incivo, is a pharmaceutical drug for the treatment of hepatitis C co-developed by Vertex Pharmaceuticals and Johnson & Johnson. It is a member of a class of antiviral drugs known as protease inhibitors. Specifically, telaprevir inhibits the hepatitis C viral enzyme NS3/4A serine protease. Telaprevir is only indicated for use against hepatitis C genotype 1 viral infections and has not been proven to be safe or effective when used for other genotypes of the virus. The standard therapy of pegylated interferon and ribavirin is less effective than telaprevir in those with genotype 1.

<span class="mw-page-title-main">Hepatitis C virus nonstructural protein 5A</span>

Nonstructural protein 5A (NS5A) is a zinc-binding and proline-rich hydrophilic phosphoprotein that plays a key role in Hepatitis C virus RNA replication. It appears to be a dimeric form without trans-membrane helices.

A hepatitis C vaccine, a vaccine capable of protecting against the hepatitis C virus (HCV), is not yet available. Although vaccines exist for hepatitis A and hepatitis B, development of an HCV vaccine has presented challenges. No vaccine is currently available, but several vaccines are currently under development.

<span class="mw-page-title-main">Ciluprevir</span> Chemical compound

Ciluprevir was a drug used experimentally in the treatment of hepatitis C. It is manufactured by Boehringer Ingelheim and developed under the research code of BILN 2061. It was the first-in-class NS3/4A protease inhibitor to enter clinical development and tested in human. Ciluprevir is a potent competitive reversible inhibitor of NS3/4A protease from HCV genotype 1a (Ki = 0.3 nM) and 1b (Ki = 0.66 nM). It shows good selectivity for NS3 protease against representative serine and cysteine proteases, human leukocyte elastase and cathepsin B (IC50 > 30 μM).

<span class="mw-page-title-main">Simeprevir</span> Chemical compound

Simeprevir, sold under the brand name Olysio among others, is a medication used in combination with other medications for the treatment of hepatitis C. It is specifically used for hepatitis C genotype 1 and 4. Medications it is used with include sofosbuvir or ribavirin and peginterferon-alfa. Cure rates are in 80s to 90s percent. It may be used in those who also have HIV/AIDS. It is taken by mouth once daily for typically 12 weeks.

Ledipasvir is a drug for the treatment of hepatitis C that was developed by Gilead Sciences. After completing Phase III clinical trials, on February 10, 2014, Gilead filed for U.S. approval of a ledipasvir/sofosbuvir fixed-dose combination tablet for genotype 1 hepatitis C. The ledipasvir/sofosbuvir combination is a direct-acting antiviral agent that interferes with HCV replication and can be used to treat patients with genotypes 1a or 1b without PEG-interferon or ribavirin.

<span class="mw-page-title-main">Paritaprevir</span> Chemical compound

Paritaprevir is an acylsulfonamide inhibitor of the NS3-4A serine protease manufactured by Abbott Laboratories that shows promising results as a treatment of hepatitis C. When given in combination with ritonavir and ribavirin for 12 weeks, the rate of sustained virologic response at 24 weeks after treatment has been estimated to be 95% for those with hepatitis C virus genotype 1. Resistance to treatment with paritaprevir is uncommon, because it targets the binding site, but has been seen to arise due to mutations at positions 155 and 168 in NS3.

Ombitasvir is an antiviral drug for the treatment of hepatitis C virus (HCV) infection by AbbVie. In the United States, it is approved by the Food and Drug Administration for use in combination with paritaprevir, ritonavir and dasabuvir in the product Viekira Pak for the treatment of HCV genotype 1, and with paritaprevir and ritonavir in the product Technivie for the treatment of HCV genotype 4.

<span class="mw-page-title-main">Ledipasvir/sofosbuvir</span> Medication used to treat hepatitis C

Ledipasvir/sofosbuvir, sold under the trade name Harvoni among others, is a medication used to treat hepatitis C. It is a fixed-dose combination of ledipasvir and sofosbuvir. Cure rates are 94% to 99% in people infected with hepatitis C virus (HCV) genotype 1. Some evidence also supports use in HCV genotype 3 and 4. It is taken daily by mouth for 8–24 weeks.

Ombitasvir/paritaprevir/ritonavir, sold under the brand name Technivie among others, is a medication used to treat hepatitis C. It is a fixed-dose combination of ombitasvir, paritaprevir, and ritonavir. Specifically it is used together with dasabuvir or ribavirin for cases caused by hepatitis C virus genotype 1 or 4. Cure rates are around 95%. It is taken by mouth.

<span class="mw-page-title-main">Grazoprevir</span> Drug approved for the treatment of hepatitis C

Grazoprevir is a drug approved for the treatment of hepatitis C. It was developed by Merck and completed Phase III trials, used in combination with the NS5A replication complex inhibitor elbasvir under the trade name Zepatier, either with or without ribavirin.

<span class="mw-page-title-main">Elbasvir</span> Chemical compound

Elbasvir is a drug approved by the FDA in January 2016 for the treatment of hepatitis C. It was developed by Merck and completed Phase III trials, used in combination with the NS3/4A protease inhibitor grazoprevir under the trade name Zepatier, either with or without ribavirin.

Elbasvir/grazoprevir, sold under the brand name Zepatier, is a fixed-dose combination for the treatment of hepatitis C, containing elbasvir and grazoprevir. It is used to treat chronic hepatitis C virus (HCV) genotypes 1 or 4 infection in both treatment-naïve and treatment-experienced patients.

<span class="mw-page-title-main">Discovery and development of NS5A inhibitors</span>

Nonstructural protein 5A (NS5A) inhibitors are direct acting antiviral agents (DAAs) that target viral proteins, and their development was a culmination of increased understanding of the viral life cycle combined with advances in drug discovery technology. However, their mechanism of action is complex and not fully understood. NS5A inhibitors were the focus of much attention when they emerged as a part of the first curative treatment for hepatitis C virus (HCV) infections in 2014. Favorable characteristics have been introduced through varied structural changes, and structural similarities between NS5A inhibitors that are clinically approved are readily apparent. Despite the recent introduction of numerous new antiviral drugs, resistance is still a concern and these inhibitors are therefore always used in combination with other drugs.

<span class="mw-page-title-main">Narlaprevir</span> Chemical compound

Narlaprevir, is an inhibitor of NS3/4A serine protease, intended for the treatment of chronic hepatitis C caused by genotype 1 virus in combination with other antiviral drugs.

<span class="mw-page-title-main">Danoprevir</span> Medication

Danoprevir (INN) is an orally available 15-membered macrocyclic peptidomimetic inhibitor of NS3/4A HCV protease. It contains acylsulfonamide, fluoroisoindole and tert-butyl carbamate moieties. Danoprevir is a clinical candidate based on its favorable potency profile against multiple HCV genotypes 1–6 and key mutants (GT1b, IC50 = 0.2–0.4 nM; replicon GT1b, EC50 = 1.6 nM). Danoprevir has been evaluated in an open-label, single arm clinical trial in combination with ritonavir for treating COVID-19 and favourably compared to lopinavir/ritonavir in a second trial.

<span class="mw-page-title-main">Glecaprevir</span> Chemical compound

Glecaprevir (INN,) is a hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor that was identified jointly by AbbVie and Enanta Pharmaceuticals. It is being developed as a treatment of chronic hepatitis C infection in co-formulation with an HCV NS5A inhibitor pibrentasvir. Together they demonstrated potent antiviral activity against major HCV genotypes and high barriers to resistance in vitro.

Sofosbuvir/velpatasvir, sold under the brand name Epclusa among others, is a fixed-dose combination medication for the treatment of hepatitis C in adults. It combines sofosbuvir and velpatasvir. It is more than 90% effective for hepatitis C genotypes one through six. It also works for hepatitis C in those who also have cirrhosis or HIV/AIDS. It is taken by mouth.

References

  1. ↑ "Glecaprevir / pibrentasvir (Mavyret) Use During Pregnancy". Drugs.com. 10 October 2019. Retrieved 30 March 2020.
  2. ↑ "Maviret 100 mg/40 mg Film-coated Tablets - Summary of Product Characteristics (SmPC)". (emc). 11 March 2020. Retrieved 30 March 2020.
  3. 1 2 3 4 5 6 "Maviret EPAR". European Medicines Agency (EMA). 17 August 2017. Retrieved 30 March 2020.
  4. 1 2 3 4 5 "Mavyret- glecaprevir and pibrentasvir tablet, film coated". DailyMed. 28 January 2020. Retrieved 30 March 2020.
  5. 1 2 "FDA approves Mavyret for Hepatitis C" (Press release). U.S. Food and Drug Administration (FDA). 3 August 2017.
  6. 1 2 3 4 5 "FDA approves treatment for adults and children with all genotypes of hepatitis C and compensated cirrhosis that shortens duration of treatment to eight weeks". U.S. Food and Drug Administration (FDA). 26 September 2019. Retrieved 1 October 2019.
  7. 1 2 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 620. ISBN   9780857113382.
  8. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  9. 1 2 3 4 "Drugs@FDA: FDA Approved Drug Products". Food and Drug Administration (FDA). Retrieved 31 October 2017.
  10. ↑ Lawitz EJ, O'Riordan WD, Asatryan A, Freilich BL, Box TD, Overcash JS, et al. (December 2015). "Potent Antiviral Activities of the Direct-Acting Antivirals ABT-493 and ABT-530 with Three-Day Monotherapy for Hepatitis C Virus Genotype 1 Infection". Antimicrobial Agents and Chemotherapy. 60 (3): 1546–1555. doi:10.1128/AAC.02264-15. PMC   4775945 . PMID   26711747.
  11. ↑ "Enanta Pharmaceuticals Form 10-Q". EDGAR . U.S. Securities and Exchange Commission. Retrieved 1 November 2017.
  12. ↑ Ng TI, Krishnan P, Pilot-Matias T, Kati W, Schnell G, Beyer J, et al. (May 2017). "In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS5A Inhibitor Pibrentasvir". Antimicrobial Agents and Chemotherapy. 61 (5). doi:10.1128/AAC.02558-16. PMC   5404558 . PMID   28193664.
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